T-Cell Depletion, Donor Hematopoietic Stem Cell Transplant (HSCT), and T-Cell Infusions in Treating Patients With Hematologic Cancer or Other Diseases

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00589602
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 131
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing the T cells from the donor cells before transplant may stop this from happening. Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help destroy any remaining cancer cells (graft-versus-tumor effect).

PURPOSE: This phase II trial is studying T-cell depletion in donor stem cell transplant followed by delayed T cell infusions in treating patients with hematologic cancer or other disease.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Malignant Plasma Cell Neoplasms; Myelodysplastic Syndromes; Precancerous/Nonmalignant Condition; Secondary Myelofibrosis	Procedure: peripheral blood lymphocyte therapy; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: total-body irradiation (TBI)	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine if T-cell depletion of a peripheral blood progenitor cell (PBPC) graft followed by delayed add-backs of defined doses of donor lymphocytes decreases the rate of graft-versus-host disease and its complications in matched unrelated donor (MUD) allogeneic peripheral blood progenitor cell (PBPC) transplantation in patients with hematologic cancers or other diseases.

• Determine whether targeted T-cell dosages in the PBPC graft can be achieved in these patients by positive CD34+ selection using the Baxter Inc. Isolex 300i v. 2.5.

• Determine the effects of T-cell depletion on the rate of engraftment in these patients.

• Develop a matched unrelated donor (MUD) allogeneic transplantation regimen that will decrease overall treatment-related mortality in these patients.

OUTLINE: This is a non-randomized study.

• Myeloablative preparative regimen: Patients receive cyclophosphamide IV once daily on days -5 and -4 followed by total body irradiation twice daily on days -3, -2, and -1. Patients also receive tacrolimus on day -1 administered by continuous IV infusion over 24 hours.

• Peripheral blood progenitor cell graft transplantation: Patients receive T-cell depleted, peripheral blood progenitor cells (PBPC) by IV infusion on day 0. Beginning 1 day after completion of the PBPC infusion, patients receive filgrastim (G-CSF) subcutaneously once daily until blood counts recover.

• Post transplantation T cell add-backs: Patients receive defined doses of donor T cells by IV infusion on days 45 and 100, in the absence of active graft-versus-host disease (GVHD) requiring steroids*.

NOTE: *A T cell add-back may be given in the presence of GVHD, if the investigator considers the risk from relapse or overwhelming viral infection to outweigh the risk of exacerbating GVHD.

Patients will be followed periodically for relapse and survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Allogeneic Hematopoietic Stem Cell TransplantationAllogeneic Hematopoietic Stem Cell Transplantation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Feasibility Study of T-Cell Depletion in Allogeneic Unrelated Bone Marrow Transplantation (MUD ALLO BMT) Followed by Delayed T-Cell Infusions
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: T-Cell Depletion Transplant Our protocol is designed to attempt to improve the current results of matched unrelated donor (MUD) allo bone marrow transplant (BMT) and will be a major step towards the introduction and refinement of graft engineering. Our approach will address in a rational fashion all major technical and clinical aspects of MUD allo BMT. Peripheral blood lymphocyte therapy; cyclophosphamide, tacrolimus, peripheral blood stem cell transplantation; total-body irradiation; 'allogeneic hematopoietic stem cell transplantation'

Procedure: peripheral blood lymphocyte therapy; T-cell depletion will be accomplished using CD34 selection with the Baxter Isolex 300i v. 2.5 device. The desirable T-cell dose will be >0.5 x 105 but <1.0 x 105 CD3+ cells per kg. The targeted CD34 cell dose will be >2 x 106 cells/kg.; Other Names: T-cell depletion ; Procedure: allogeneic hematopoietic stem cell transplantation; Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: peripheral blood stem cell transplantation; Peripheral blood stem cell transplantation; Radiation: total-body irradiation (TBI); Treatment will be delivered using 6MV photons twice daily for 3 days

Outcome Measures

Primary Outcome Measures

1. Treatment-related Mortality (TRM) [180 days after transplant]

   The complication rate in matched unrelated donor (MUD) allogeneic bone marrow transplant (allo BMT) is known to be high. Graft failure and severe graft versus host disease (GvHD) are the most significant contributors to treatment related mortality (TRM). This treatment regimen will be considered unacceptable if the number of patients that experience TRM is 55% or greater, and effective if TRM is 33% or less.

Secondary Outcome Measures

1. The Rate of Acute Graft Versus Host Disease (GVHD) [D+100 from transplant]

2. Number of Participants With Duration of Absolute Neutropenia [D+100 from transplant]

3. Number of Participants Able to Receive T-cell Add Backs [through D+100]

   Patients receive defined doses of donor T cells by IV infusion on days 45 and 100, in absence of active graft-versus-host disease (GVHD) requiring steroids.

4. Number of Participants With Relapse-free Survival [after 7 years of follow up]

   number of patients that were still alive and relapse free

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of any of the following hematologic cancers or other diseases:

• Acute myelogenous leukemia

• Relapsed or refractory disease with poor-risk cytogenetics

• Acute lymphoblastic leukemia

• Relapsed or refractory disease with poor-risk cytogenetics

• Chronic myelogenous leukemia

• Persistent disease after at least 6 months of treatment with imatinib mesylate (Gleevec)

• Myelodysplasia, meeting 1 of the following criteria:

• French-American-British Classification of refractory anemia with excess blasts (RAEB) or RAEB with transformation

• International Prognostic Scoring System score > 2

• Lymphoid malignancies, including non-Hodgkin lymphoma, Hodgkin disease, chronic lymphocytic leukemia, and prolymphocytic leukemia

• Relapsed or refractory disease after at least 1 prior therapy

• Myelofibrosis

• Transfusion dependent (RBC's, platelets, or both)

• Paroxysmal nocturnal hemoglobinuria (transfusion dependent)

• Myeloproliferative disorder

• Eosinophilic leukemia

• Severe aplastic anemia

• Corrected reticulocyte count < 1%

• Platelet count < 30,000/mm³ (untransfused)

• Bone marrow biopsy with < 15% cellularity

• Plasma cell leukemia

• No essential thrombocytopenia or polycythemia vera

• No matched related donor available

• Must have an 8/8 or 7/8 serologic HLA matched unrelated donor available

PATIENT CHARACTERISTICS:

• Cardiac ejection fraction ≥ 45% (if < 45%, then cardiac consult required)

• Not pregnant or nursing

• Negative pregnancy test

• FEV_1 and DLCO ≥ 45% predicted

• Creatinine < 2.0 mg/dL

• Bilirubin < 2.0 mg/dL

• HIV negative

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior allogeneic bone marrow transplantation

• No concurrent administration of steroids with T-cell add-backs

INCLUSION CRITERIA:

• Patient actual weight must not be greater than 1.5x their ideal body weight

• Cardiac ejection fraction >45%. If less than 45%, a Cardiac consult will be obtained.

• A suitably matched unrelated donor that is at least a 7 out of 8 HLA serologic match.

• Patient is not pregnant.

• FEV 1 and DLCO > 45% predicted on pulmonary function testing.

• Serum creatinine <2.0 mg/dl, serum bilirubin <2.0 mg/dl.

• Patient and donor are HIV negative.

• Diagnosis of one of the following diseases

• Acute myelogenous leukemia

• Relapsed disease,

• Refractory disease, or

• With poor-risk cytogenetics

• Acute lymphoblastic leukemia

• Relapsed disease,

• Refractory disease, or

• With poor-risk cytogenetics

• Chronic myelogenous leukemia

• Persistent disease after at least 6 months of treatment with Imatinib Mesylate (Gleevec)

• Myelodysplasia

• FAB Classification of RAEB or RAEB-T -Or-

• IPSS score >2

• Lymphoid malignancies, including non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia and prolymphocytic leukemia

• Relapsed or refractory disease after at least 1 prior therapy

• Myelofibrosis

• Transfusion dependence (RBC's, platelets, or both)

• Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Transfusion dependent

• Myeloproliferative Disorder

• Eosinophilic Leukemia

• Severe aplastic anemia (<1% corrected reticulocyte count, <30,000 untransfused platelet count, bone marrow biopsy with <15% cellularity)

• Plasma cell leukemia

• Patients with ET or PV will not be candidates unless their disease has transformed to end stage myelofibrosis or acute leukemia, for which eligibility criteria for myelofibrosis or acute leukemia would apply.

• Patient must signed written informed consent.

EXCLUSION CRITERIA:

• Inability to give informed consent

• Absence of any of the above mentioned medical conditions

• Availability of matched-related donor

• History of prior allogeneic BMT

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Brian J. Bolwell, MD, The Cleveland Clinic
• Principal Investigator: Jarek Maciejewski, MD, PhD, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jaroslaw Maciejewski, Department Chair of Translational Hematology and Oncology Research, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT00589602
• Other Study ID Numbers: CCF-6501; P30CA043703
• First Posted: Jan 9, 2008
• Last Update Posted: May 30, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jaroslaw Maciejewski, Department Chair of Translational Hematology and Oncology Research, The Cleveland Clinic: Adult leukemia; lymphoma; myelodysplastic syndromes; plasma cell disorders
• Additional relevant MeSH terms: Multiple Myeloma; Preleukemia; Neoplasms, Plasma Cell; Plasmacytoma; Precancerous Conditions; Myelodysplastic Syndromes; Myeloproliferative Disorders

Study Results

Participant Flow

Recruitment Details	Patients were recruited from local hospital from January, 2006 through January, 2009.

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	Our protocol is designed to attempt to improve the current results of MUD allo BMT and will be a major step towards the introduction and refinement of graft engineering. Our approach will address in a rational fashion all major technical and clinical aspects of MUD allo BMT. Peripheral blood lymphocyte therapy; cyclophosphamide, tacrolimus, peripheral blood stem cell transplantation; total-body irradiation; 'allogeneic hematopoietic stem cell transplantation' peripheral blood lymphocyte therapy: T-cell depletion cyclophosphamide: T-cell depletion tacrolimus: T-cell depletion allogeneic hematopoietic stem cell transplantation: T-cell depletion peripheral blood stem cell transplantation: T-cell depletion total-body irradiation: T-cell depletion
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	Our protocol is designed to attempt to improve the current results of MUD allo BMT and will be a major step towards the introduction and refinement of graft engineering. Our approach will address in a rational fashion all major technical and clinical aspects of MUD allo BMT. Peripheral blood lymphocyte therapy; cyclophosphamide, tacrolimus, peripheral blood stem cell transplantation; total-body irradiation; 'allogeneic hematopoietic stem cell transplantation' peripheral blood lymphocyte therapy: T-cell depletion cyclophosphamide: T-cell depletion tacrolimus: T-cell depletion allogeneic hematopoietic stem cell transplantation: T-cell depletion peripheral blood stem cell transplantation: T-cell depletion total-body irradiation: T-cell depletion
Overall Participants	13
Age (Count of Participants)
<=18 years	1 7.7%
Between 18 and 65 years	12 92.3%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46
Sex: Female, Male (Count of Participants)
Female	7 53.8%
Male	6 46.2%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Treatment-related Mortality (TRM)
Description	The complication rate in matched unrelated donor (MUD) allogeneic bone marrow transplant (allo BMT) is known to be high. Graft failure and severe graft versus host disease (GvHD) are the most significant contributors to treatment related mortality (TRM). This treatment regimen will be considered unacceptable if the number of patients that experience TRM is 55% or greater, and effective if TRM is 33% or less.
Time Frame	180 days after transplant

Outcome Measure Data

Analysis Population Description

Patients that received treatment

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	Our protocol is designed to attempt to improve the current results of MUD allo BMT and will be a major step towards the introduction and refinement of graft engineering. Our approach will address in a rational fashion all major technical and clinical aspects of MUD allo BMT. Peripheral blood lymphocyte therapy; cyclophosphamide, tacrolimus, peripheral blood stem cell transplantation; total-body irradiation; 'allogeneic hematopoietic stem cell transplantation' peripheral blood lymphocyte therapy: T-cell depletion cyclophosphamide: T-cell depletion tacrolimus: T-cell depletion allogeneic hematopoietic stem cell transplantation: T-cell depletion peripheral blood stem cell transplantation: T-cell depletion total-body irradiation: T-cell depletion
Measure Participants	12
Number [participants]	8 61.5%

2. Secondary Outcome

Title	The Rate of Acute Graft Versus Host Disease (GVHD)
Time Frame	D+100 from transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	Our protocol is designed to attempt to improve the current results of matched unrelated donor allogeneic bone marrow transplant (MUD allo BMT) and will be a major step towards the introduction and refinement of graft engineering. Our approach will address in a rational fashion all major technical and clinical aspects of MUD allo BMT. Peripheral blood lymphocyte therapy; cyclophosphamide, tacrolimus, peripheral blood stem cell transplantation; total-body irradiation; allogeneic hematopoietic stem cell transplantation; peripheral blood lymphocyte therapy: T-cell depletion cyclophosphamide: T-cell depletion tacrolimus: T-cell depletion allogeneic hematopoietic stem cell transplantation: T-cell depletion peripheral blood stem cell transplantation: T-cell depletion total-body irradiation: T-cell depletion
Measure Participants	12
Number [participants]	11 84.6%

3. Secondary Outcome

Title	Number of Participants With Duration of Absolute Neutropenia
Time Frame	D+100 from transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	peripheral blood lymphocyte therapy: T-cell depletion will be accomplished using CD34 selection with the Baxter Isolex 300i v. 2.5 device. The desirable T-cell dose will be >0.5 x 105 but <1.0 x 105 CD3+ cells per kg. The targeted CD34 cell dose will be >2 x 106 cells/kg. cyclophosphamide: Cyclophosphamide 60 mg/kg/d for 2 days on Day -5 and Day -4 tacrolimus: tacrolimus on day -1 administered by continuous IV infusion over 24 hours allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation total-body irradiation (TBI): Treatment will be delivered using 6MV photons twice daily for 3 days
Measure Participants	12
Number [participants]	10 76.9%

4. Secondary Outcome

Title	Number of Participants Able to Receive T-cell Add Backs
Description	Patients receive defined doses of donor T cells by IV infusion on days 45 and 100, in absence of active graft-versus-host disease (GVHD) requiring steroids.
Time Frame	through D+100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	peripheral blood lymphocyte therapy: T-cell depletion will be accomplished using CD34 selection with the Baxter Isolex 300i v. 2.5 device. The desirable T-cell dose will be >0.5 x 105 but <1.0 x 105 CD3+ cells per kg. The targeted CD34 cell dose will be >2 x 106 cells/kg. cyclophosphamide: Cyclophosphamide 60 mg/kg/d for 2 days on Day -5 and Day -4 tacrolimus: tacrolimus on day -1 administered by continuous IV infusion over 24 hours allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation total-body irradiation (TBI): Treatment will be delivered using 6MV photons twice daily for 3 days
Measure Participants	12
Number [participants]	3 23.1%

5. Secondary Outcome

Title	Number of Participants With Relapse-free Survival
Description	number of patients that were still alive and relapse free
Time Frame	after 7 years of follow up

Outcome Measure Data

Analysis Population Description

All patients that received treatment

Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	peripheral blood lymphocyte therapy: T-cell depletion will be accomplished using CD34 selection with the Baxter Isolex 300i v. 2.5 device. The desirable T-cell dose will be >0.5 x 105 but <1.0 x 105 CD3+ cells per kg. The targeted CD34 cell dose will be >2 x 106 cells/kg. cyclophosphamide: Cyclophosphamide 60 mg/kg/d for 2 days on Day -5 and Day -4 tacrolimus: tacrolimus on day -1 administered by continuous IV infusion over 24 hours allogeneic hematopoietic stem cell transplantation peripheral blood stem cell transplantation total-body irradiation (TBI): Treatment will be delivered using 6MV photons twice daily for 3 days
Measure Participants	12
Number [participants]	2 15.4%

Adverse Events

Time Frame	Adverse events data was over the course of the study for approximately 7 years
Arm/Group Title	T-Cell Depletion Transplant
Arm/Group Description	peripheral blood lymphocyte therapy: T-cell depletion cyclophosphamide: T-cell depletion tacrolimus: T-cell depletion allogeneic hematopoietic stem cell transplantation: T-cell depletion peripheral blood stem cell transplantation: T-cell depletion total-body irradiation: T-cell depletion
All Cause Mortality
	T-Cell Depletion Transplant
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	T-Cell Depletion Transplant
	Affected / at Risk (%)	# Events
Total	9/12 (75%)
General disorders
Death by Relapse	4/12 (33.3%)	4
Death from Acute GVHD	3/12 (25%)	3
Infections and infestations
Death due to Infection	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Death due to respiratory failure	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	T-Cell Depletion Transplant
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Hospitalized for TTP (Thrombotic Thrombocytopenic Purpura)	1/12 (8.3%)	1
Cardiac disorders
Hospitalized for chest pains	1/12 (8.3%)	1
Endocrine disorders
Hospitalized with hypoglycemia	1/12 (8.3%)	1
Gastrointestinal disorders
Hospitalized for abdominal pain	2/12 (16.7%)	4
Hospitalized for blood in stool and	1/12 (8.3%)	2
Constipation	1/12 (8.3%)	1
General disorders
Hospitalization for fever	7/12 (58.3%)	24
Hospitalized with GVHD	7/12 (58.3%)	11
Hospitalized for Nausae, Vomiting and Diarrhea	5/12 (41.7%)	22
Hospitalized for broken leg	1/12 (8.3%)	1
Hospitalized for hypertension	1/12 (8.3%)	1
Hospitalized for Syncope and dizziness	1/12 (8.3%)	1
Hospitalized for puritus and plolyarthagias	1/12 (8.3%)	1
Hospitalized for relapse of disease	1/12 (8.3%)	1
Hospitalized for numbness in hands and feet	1/12 (8.3%)	1
Infections and infestations
Hospitalized with Infection	9/12 (75%)	38
Hospitalized for abscess	2/12 (16.7%)	2
Injury, poisoning and procedural complications
Hospitalized for a motor vehicle accident	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Hospitalized for muscle spasms	1/12 (8.3%)	2
Hospitalized for necrosis of knees	1/12 (8.3%)	1
Nervous system disorders
Hospitalized with mental status changes	2/12 (16.7%)	2
Renal and urinary disorders
Hospitalized for dysuria	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Hospitalized for respiratory distress	1/12 (8.3%)	1
Hospitalized for shortness of breath	1/12 (8.3%)	1
Hospitalized for pulmonary embolism	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Hospitalized for mucocitus and rash	1/12 (8.3%)	2
Surgical and medical procedures
Hospitalized for knee replacement	1/12 (8.3%)	2
Hospitalized for surgery medial epicondylitis	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.